TECHNICAL FIELD
1. Field of the Invention
The present invention relates to cephem derivatives or pharmaceutically acceptable salts thereof useful as antibacterial agents and represented by the formula I: ##STR4##
wherein ##STR5##
represents benzene ring, pyridine ring, pyrazine ring or 5-membered aromatic heterocycle (having one oxygen or sulfur atom as ring-constituting atom); PA1 X and Y respectively represent hydrogen atom or CXY represents C.dbd.N--OR.sub.5 wherein R.sub.5 represents hydrogen atom, halo C.sub.1 -C.sub.6 alkyl or C.sub.3 -C.sub.7 cycloalkyl; PA1 R.sub.1 represents phenyl, furyl, thienyl, thiazolyl (which may be substituted with amino group), tetrazolyl or thiadiazolyl, PA1 R.sub.2, R.sub.3 and R.sub.4 respectively represent hydrogen atom, halogen, hydroxyl group, nitro, C.sub.1 -C.sub.6 alkoxy, trifluoromethyl, isothiuronium C.sub.1 -C.sub.6 alkyl, amino C.sub.1 -C.sub.6 alkyl, halo C.sub.1 -C.sub.6 alkyl, morpholino, piperidino or piperazinyl, there being no R.sub.4 where ##STR6## PA1 represents 5-membered aromatic heterocycle; or synthetic intermediates of the compounds of the formula I and represented by the formula II ##STR7## PA1 is 5-membered aromatic heterocycle, the thiopyranyl group with condensed ring may be a group with any of the following structures. ##STR10## PA1 wherein R.sub.2 and R.sub.3 are as defined above.
wherein Z represents a protective group for a carboxyl group and ##STR8## PA2 R.sub.2, R.sub.3 and R.sub.4 are as defined above.
2. Description of the Background
In recent years, hardly-curable infections due to pathogenic bacteria having resistance against antibiotics such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) have caused serious problems. Vancomycin, which was the only agent against which no resistant bacteria had been found, was frequently used as medicine against MRSA; however, recently, vancomycin-resistant Staphylococcus aureus (MU3) was found.
Among the above-mentioned resistant bacteria, MRSA are typical as hospital infecting bacteria and there are MRSA-carriers in healthy humans. Usually, these healthy MRSA-carriers are not sick with MRSA; however, they may tend to become sick with MRSA when they have come into compromised hosts with reduced vital resistance due to operations or other diseases. Once they become sick, a remedy for their sickness is difficult to effect. Nowadays, arbekacin, which is an aminoglycoside, and vancomycin, which is a glycopeptide, are used for such diseases. However, already, there are resistant bacteria against arbekacin; and resistant bacteria such as the above-mentioned MU3 have been found also as to vancomycin only against which there were no resistant bacteria. Such vancomycin-resistant MRSA are found all over Japan so that there is a fear that, in near feature, MRSA infectious diseses will increase which cannot be treated with vancomycin.
Although VRE provide world-shaking issues, though they have not been found in Japan yet. VRE are bacteria which have resistance against various antibacaterial agents just as MRSA and which derive from enterococci (E. faecalis and E. faecium) against which in turn only vancomycin was effective and which have gained high resistance against vancomycin, too. It is highly feared that, in the future, VRE will appear in Japan or prevail as imported infections. However, no effective medicines are present now and have been developed yet.
Coming of such medical crisis is readily predicted and urgent development of medicines effective for the resistant bacteria is desired to avert such crisis.
Cephem-type antibiotics have been proposed as new antibiotics effective for MRSA. More specifically, cephem derivatives having cyclic ammoniothiovinyl group at the 3-position have been proposed (Japanese Patent Provisional publication (Kokai) Nos. 6-206886 and 7-304779). These compounds are defective both in terms of antibacterial force and toxicity, perhaps, due to the cyclic ammoniothiovinyl group, thus failing to provide new medicines.